WO2013056070A2 - Heterocyclic compounds and methods of use thereof - Google Patents

Heterocyclic compounds and methods of use thereof Download PDF

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Publication number
WO2013056070A2
WO2013056070A2 PCT/US2012/059983 US2012059983W WO2013056070A2 WO 2013056070 A2 WO2013056070 A2 WO 2013056070A2 US 2012059983 W US2012059983 W US 2012059983W WO 2013056070 A2 WO2013056070 A2 WO 2013056070A2
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WO
WIPO (PCT)
Prior art keywords
benzo
methyl
amino
thiazol
cyclohexanol
Prior art date
Application number
PCT/US2012/059983
Other languages
English (en)
French (fr)
Other versions
WO2013056070A3 (en
Inventor
Michael J. Hadd
Michael D. Hocker
Mark W. Holladay
Gang Liu
Martin W. Rowbottom
Shimin Xu
Original Assignee
Ambit Biosciences Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to BR112014009006A priority Critical patent/BR112014009006B8/pt
Priority to DK12780613.1T priority patent/DK2766359T5/en
Application filed by Ambit Biosciences Corporation filed Critical Ambit Biosciences Corporation
Priority to EP12780613.1A priority patent/EP2766359B9/en
Priority to CA2851155A priority patent/CA2851155C/en
Priority to KR1020147012791A priority patent/KR102066297B1/ko
Priority to MX2014004252A priority patent/MX368081B/es
Priority to AU2012322095A priority patent/AU2012322095B2/en
Priority to SI201230628A priority patent/SI2766359T1/sl
Priority to RS20160502A priority patent/RS54936B1/sr
Priority to RU2014119244A priority patent/RU2648997C2/ru
Priority to CN201280062194.7A priority patent/CN104066730B/zh
Priority to NZ623274A priority patent/NZ623274B2/en
Priority to IN3597CHN2014 priority patent/IN2014CN03597A/en
Priority to SG11201401236XA priority patent/SG11201401236XA/en
Priority to ES12780613.1T priority patent/ES2586527T3/es
Priority to JP2014535928A priority patent/JP6162130B2/ja
Publication of WO2013056070A2 publication Critical patent/WO2013056070A2/en
Publication of WO2013056070A3 publication Critical patent/WO2013056070A3/en
Priority to IL231927A priority patent/IL231927A/en
Priority to ZA2014/02549A priority patent/ZA201402549B/en
Priority to PH12014500794A priority patent/PH12014500794B1/en
Priority to HK15101155.2A priority patent/HK1200814A1/zh
Priority to PH12015501955A priority patent/PH12015501955A1/en
Priority to HRP20160744TT priority patent/HRP20160744T2/hr
Priority to CY20161100640T priority patent/CY1117745T1/el
Priority to SM201600223T priority patent/SMT201600223B/it

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/52—Purines, e.g. adenine
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • heterocyclic compounds including benzothiazolyl, benzoxazolyl, and quinazolyl compounds.
  • the compounds are modulators of type III receptor tyrosine kinase family.
  • the compounds are modulators of CSFIR, FLT3, KIT, and/or PDGFR kinases.
  • compositions comprising the compounds and methods of use thereof. The compounds provided are useful in the treatment, prevention, or amelioration of a disease or disorder related to CSFIR, FLT3, KIT, and/or PDGFR kinase activity or one or more symptoms associated with such diseases or disorders.
  • PKs Protein kinases
  • RTKs Receptor tyrosine kinases
  • PDGFR a PDGFR ⁇ , FLT3, KIT, VEGFR and CSFIR, has been implicated in various proliferative and inflammatory diseases.
  • CSFIR also known as macrophage colony stimulating factor receptor
  • M-CSFR macrophage colony stimulating factor
  • CSF-1 macrophage colony stimulating factor
  • Activation of CSFIR leads to the proliferation, survival, motility and differentiation of cells of the monocyte/macrophage lineage and hence plays a role in normal tissue development and immune defense.
  • Activation of CSFIR also leads to the proliferation and differentiation of osteoclast precursors and therefore mediates the process of bone resorption.
  • CSF1R is believed to be an important therapeutic target for osteoporosis and inflammatory arthritis.
  • elevated M-CFS signaling leads to elevated osteoclast activity, which leads to bone loss attending arthritis and other inflammatory bone erosion.
  • CSF1R therefore represents a promising therapeutic approach for arthritis and other inflammatory bone erosion which is further supported by the efficacy data of known CSF1R inhibitors such as Ki-20227 and GW2580 in arthritic animal models (See Conwat et al. JP£T2008, 326:41-50 and Ohno et al. Eur. J. Immunol. 2008, 38:283-291). Dysregulation of osteoclast development and disruption in the balance of bone resorption and bone formation that underlie osteoporosis might also be treated with a modulator of CSF1R.
  • CSF1R may be a valuable therapeutic target for these solid tumors.
  • M-CSF is one of several cytokines implicated in the recruitment of tumor-associated macrophages (TAMs) that contribute to tumor angiogenesis and tumor progression to metastasis, and more recently, that the preclinical inhibitor GW2580 inhibits tumor metastasis and angiogenesis in mice tumor xenograft experiments (Priceman et al. Blood 2010 115(7): 1461-1471).
  • TAMs tumor-associated macrophages
  • Stimulated osteoclast activity is also believed to underlie the pathophysiology of bone metastases. (Lipton, J. Support. Oncol. 2004 2:205-220). Metastatic bone lesions results in significant localized bone loss and lead to skeletal morbidity, symptoms which include bone pain, bone fractures and hypercalcemia. Inhibition of CSF1R therefore may therefore provide therapy for solid tumors and metastatic cancer including metastases to the bone.
  • FLT3 Another member of the PDGFR family, FLT3 (also called Flk2), plays an important role in the proliferation and differentiation of hematopoietic stem cells and activating mutation or overexpression of this receptor is found in AML (See, Heinrich Mini-Reviews in Medicinal Chemistry 2004, 4(3):255-271, Kiyoi et al. IntJ Hematol, 2005 82:85-92). More than a dozen known FLT3 inhibitors are being developed and some have shown promising clinical effects against AML (See Levis et al. Int J Hematol. 2005 82:100-107).
  • the FLT3 receptor is also expressed in a large portion of dendritic cell progenitors and stimulation of the receptor causes the proliferation and differentiation of these progenitors into dendritic cells (DC). Since dendritic cells are the main initiators of the T-cell mediated immune response, including the autoreactive immune response, FLT3 inhibition is a mechanism for downregulating DC-mediated inflammatory and autoimmune responses.
  • EAE experimental autoimmune encephalomyelitis
  • a high level of the FLT3 ligand is found in the serum of patients with Langerhans cell histiocytosis and systemic lupus erythematosus, which further implicates FLT3 signaling in the dysregulation of dendritic cell progenitors in those autoimmune diseases (See Rolland et al. J. Immunol. 2005 174:3067-3071).
  • GIST gastrointestinal stromal tumors
  • Gain of function mutations of the Kit receptor are also associated with mast cell/myeloid leukemia and seminomas/dysgerminomas (Blume -Jensen Nature 2001 411(17): 355-365. KIT mutations have been also identified in certain melanomas and is recognized as a potential therapeutic target for melanoma (Curtain et al. J Clin. Oncol. 2006
  • the compounds have activity as CSFIR, FLT3, KIT, and/or PDGFR kinase modulators.
  • the compounds are useful in medical treatments, pharmaceutical compositions and methods for modulating the activity of CSFIR, FLT3, KIT, and/or PDGFR kinases, including wildtype and/or mutated forms of CSFIR, FLT3, KIT, and/or PDGFR kinases.
  • the compounds provided herein have activity as CSFIR, FLT3, KIT, and/or PDGFR kinase modulators.
  • the compounds for use in the compositions and methods provided herein have formula (I).
  • stereoisomers mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein:
  • R 3 is hydrogen or alkyl
  • R 4 is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, where R 4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 1 ;
  • each Q 1 is independently deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,
  • Y is -(CR 5 R 6 ) q -;
  • R 5 andR 6 are each independently hydrogen, deuterium, halo, alkyl, haloalkyl or hydroxyalkyl;
  • Z is O, S or NR 7 ;
  • R 7 is hydrogen, deuterium or alkyl
  • each W is independently CR 8 or N;
  • R 8 is hydrogen, deuterium, halo, haloalkyl or alkyl
  • ring A is a bicyclic or tricyclic aryl, heteroaryl or heterocyclyl optionally substituted with one to four substituents selected from Q 2 ;
  • W 1 is N or C
  • W 2 is N, NR 9a or CR 9b ;
  • W 3 is N, NR 10a or CR 10b ;
  • W 4 is N, NR l la or CR l lb ;
  • R 9a , R 9b , R 10a , R 10b , R l la andR l lb are selected as follows:
  • R 9a , R 10a andR l la are each independently hydrogen, deuterium or alkyl and R 9b , R 10b andR llb are each independently hydrogen or Q 2 ; or
  • R 9a and R 10b R 9a and R 10a , R 9b and R 10b , R 9b and R 10a , R 10b and R l la , R 10a and R l lb , R 10a and R l lb or R 10b and R l lb together with the atoms to which they are attached form an aryl, heteroaryl or heterocyclyl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 2 ; and the remainder of R 9a or R l la is hydrogen, deuterium or alkyl; and the remainder of R 9b or R llb is hydrogen or Q 2 ; or
  • each Q 2 is independently halo, deuterium, cyano, oxo, thioxo, alkyl, haloalkyl, haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -R u OR x , -R u OR u OR x ,-R u OR u N(R y )(R z ),
  • each R d is independently hydrogen or alkyl
  • each R u is independently alkylene, alkenylene or a direct bond
  • R w is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
  • R y and R z are each independently selected from (i) or (ii) below: (i) R y and R z are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
  • each Q 7 is independently selected from halo, deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
  • J is O, NR X or S
  • each t is independently an integer from 0-2;
  • n 1 or 2;
  • q is an integer from 0-4,
  • the compound provided herein is a compound of formula (I). In one embodiment, the compound provided herein is a pharmaceutically acceptable salt of the compound of formula (I). In one embodiment, the compound provided herein is a solvate of the compound of formula (I). In one embodiment, the compound provided herein is a hydrate of compound of formula (I). In one embodiment, the compound provided herein is a prodrug of the compound of formula (I). In one embodiment, the compound provided herein is a clathrate of the compound of formula (I).
  • the pharmaceutical compositions deliver amounts effective for the treatment, prevention, or amelioration of diseases or disorders that are modulated or otherwise affected by CSFIR, FLT3, KIT, and/or PDGFR kinases, or one or more symptoms or causes thereof.
  • Such diseases or disorders include without limitation, cancers, nonmalignant proliferation diseases, atherosclerosis, restenosis following vascular angioplasty, fibroproliferative disorders, inflammatory diseases or disorders related to immune dysfunction, infectious diseases, and/or diseases or disorders that can be treated, prevented or managed by modulating the activity, binding or sub-cellular distribution of kinases, wherein such methods comprise administering to a subject, e.g., a human, in need of such treatment, prevention or management a therapeutically and prophylactically effective amount of a compound provided herein.
  • a subject e.g., a human
  • combination therapies using one or more compounds or compositions provided herein, or pharmaceutically acceptable derivatives thereof, in combination with other pharmaceutically active agents for the treatment of the diseases and disorders described herein.
  • such additional pharmaceutical agents include one or more chemotherapeutic agents, anti-proliferative agents, anti-inflammatory agents, immunomodulatory agents or immunosuppressive agents.
  • compositions provided herein, or pharmaceutically acceptable derivatives thereof may be administered simultaneously with, prior to, or after administration of one or more of the above agents.
  • Pharmaceutical compositions containing a compound provided herein and one or more of the above agents are also provided.
  • kits for treating, preventing or ameliorating a disease or disorder that is modulated or otherwise affected by CSFIR, FLT3, KIT, and/or PDGFR kinases such as wild type and/or mutant CSFIR, FLT3, KIT, and/or PDGFR kinases, or one or more symptoms or causes thereof.
  • Fig. 1 depicts the in vivo inhibition of CSF-1 dependent M-NFS-60 tumor cell proliferation in the peritoneal cavity of athymic nu/nu mice from the
  • Fig. 2 depicts the in vivo inhibition of CSF-1 dependent M-NFS-60 tumor cell proliferation in the peritoneal cavity of athymic nu/nu mice from the
  • FIG. 4 depicts the in vivo inhibition of PTHrP -induced hypercalcemia from the administration of Compound B having the Formula I, in BDF1 mice challenged twice daily for seven days with 0.5 mg/kg recombinant PTHrP, as measured by serum TRAPC5B levels, a bone resorption marker.
  • [0027] Provided herein are compounds of formula I that have activity as CSF1R, FLT3, KIT, and/or PDGFRP kinase modulators. Further provided are methods of treating, preventing or ameliorating diseases that are modulated by CSF1R, FLT3, KIT, and/or PDGFRP kinases, and pharmaceutical compositions and dosage forms useful for such methods. The methods and compositions are described in detail in the sections below.
  • Alkyl refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten, one to eight, one to six or one to four carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (z ' so-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like.
  • alkenylene or "alkenylene chain” refers to a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from two to eight carbon atoms, wherein the unsaturation is present only as double bonds and wherein the double bond can exist between any two carbon atoms in the chain, e.g., ethenylene, prop-l-enylene, but-2-enylene and the like.
  • the alkenylene chain may be attached to the rest of the molecule through any two carbons within the chain.
  • Alkynylene or "alkynylene chain” refers to a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from two to eight carbon atoms, wherein the unsaturation is present only as triple bonds and wherein the triple bond can exist between any two carbon atoms in the chain, e.g., ethynylene, prop-l-ynylene, but-2-ynylene, pent-l-ynylene,
  • alkynylene chain may be attached to the rest of the molecule through any two carbons within the chain.
  • Alkoxy refers to the group having the formula -OR wherein R is alkyl or haloalkyl.
  • An “optionally substituted alkoxy” refers to the group having the formula - OR wherein R is an optionally substituted alkyl as defined herein.
  • Cycloalkyl refers to a stable monovalent monocyclic or bicyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, having from three to ten carbon atoms which is saturated, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl, norbornane, norbornene, adamantyl,
  • Cycloalkenyl refers to a stable monovalent monocyclic or bicyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, having from three to ten carbon atoms, which is partially unsaturated.
  • Examples of cycloalkenyl include cyclopropene, cyclobutylene, cyclopentene and cyclohexene.
  • Halo, halogen or halide refers to F, CI, Br or I.
  • Haloalkyl refers to an alkyl group, in certain embodiments, Ci_ 6 alkyl group in which one or more of the hydrogen atoms are replaced by halogen.
  • Such groups include, but are not limited to, chloromethyl, trifluoromethyl
  • Heterocycle or “Heterocyclyl” refers to a stable 3- to 15-membered non- aromatic ring radical which consists of carbon atoms and from one to five
  • the heterocyclic ring system radical may be a monocyclic, bicyclic or tricyclic ring or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen or sulfur atoms in the heterocyclic ring system radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated.
  • the heterocyclic ring system may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
  • heterocylic radicals include, morpholinyl, piperidinyl, piperazinyl, pyranyl, pyrrolidinyl, oxetanyl, azetidinyl, quinuclidinyl, octahydroquinolizinyl, decahydroquinolizinyl,
  • Heteroaryl refers to a heterocyclyl group as defined above which is aromatic.
  • the heteroaryl groups include, but are not limited to monocyclyl, bicyclyl and tricyclyl groups, and may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
  • Heterocyclylalkyl refers to a group of the formula -RaR e wherein Ra is an alkyl group as defined above and R e is a heterocyclyl group as defined herein, where the alkyl group R a may attach at either the carbon atom or the heteroatom of the heterocyclyl group R ⁇ .
  • the alkyl group and the heterocyclyl group may be optionally substituted as defined herein.
  • IC 50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as cell growth or proliferation measured via any the in vitro or cell based assay described herein.
  • Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine,
  • alkali metal salts such as but not limited to lithium, potassium and sodium
  • alkali earth metal salts such as but not limited to barium, calcium and magnesium
  • transition metal salts such as but not limited to zinc
  • other metal salts such as but not limited to sodium hydrogen phosphate and disodium phosphate
  • salts of mineral acids such as but not limited to hydrochlorides and sulfates
  • salts of organic acids such as but not limited to acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates, fumarates and organic sulfonates.
  • hydrate means a compound provided herein or a salt thereof, that further includes a stoichiometric or non-stoichiometeric amount of water bound by non-covalent intermolecular forces.
  • solvate means a solvate formed from the association of one or more solvent molecules to a compound provided herein.
  • solvate includes hydrates (e.g., mono-hydrate, dihydrate, trihydrate, tetrahydrate and the like).
  • substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC) and mass spectrometry (MS), used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance.
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • MS mass spectrometry
  • the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures.
  • the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration, or may be a mixture thereof. It is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form.
  • isotopic composition refers to the amount of each isotope present for a given atom
  • naturally occurring isotopic composition refers to the naturally occurring isotopic composition or abundance for a given atom
  • Atoms containing their natural isotopic composition may also be referred to herein as "non- enriched" atoms.
  • the atoms of the compounds recited herein are meant to represent any stable isotope of that atom. For example, unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural isotopic composition.
  • isotopically enriched refers to an atom having an isotopic composition other than the natural isotopic composition of that atom.
  • “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.
  • haloalkyl may include one or more of the same or different halogens.
  • Anti-cancer agents refers to anti-metabolites (e.g., 5-fluoro-uracil, methotrexate, fludarabine), antimicrotubule agents (e.g., vinca alkaloids such as vincristine, vinblastine; taxanes such as paclitaxel, docetaxel), alkylating agents (e.g., cyclophosphamide, melphalan, carmustine, nitrosoureas such as
  • platinum agents e.g. cisplatin, carboplatin, oxaliplatin, JM-216 or satraplatin, CI-973
  • anthracyclines e.g., doxrubicin, daunorubicin
  • antitumor antibiotics e.g., mitomycin, idarubicin, adriamycin, daunomycin
  • topoisomerase inhibitors e.g., etoposide, camptothecins
  • anti-angiogenesis agents e.g.
  • Sutent® and Bevacizumab or any other cytotoxic agents, (estramustine phosphate, prednimustine), hormones or hormone agonists, antagonists, partial agonists or partial antagonists, kinase inhibitors, and radiation treatment.
  • cytotoxic agents estramustine phosphate, prednimustine
  • hormones or hormone agonists, antagonists, partial agonists or partial antagonists kinase inhibitors
  • radiation treatment any other cytotoxic agents, (estramustine phosphate, prednimustine), hormones or hormone agonists, antagonists, partial agonists or partial antagonists, kinase inhibitors, and radiation treatment.
  • Anti-inflammatory agents refers to matrix metalloproteinase inhibitors, inhibitors of pro-inflammatory cytokines (e.g., anti-TNF molecules, TNF soluble receptors, and IL1) non-steroidal anti-inflammatory drugs (NSAIDs) such as prostaglandin synthase inhibitors (e.g., choline magnesium salicylate, salicylsalicyclic acid), COX-1 or COX-2 inhibitors), or glucocorticoid receptor agonists such as corticosteroids, methylprednisone, prednisone, or cortisone.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • R 3 is hydrogen or alkyl
  • R 4 is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, where R 4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 1 ;
  • each Q 1 is independently deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,
  • Y is -(CR 5 R 6 ) q -;
  • R 5 andR 6 are each independently hydrogen, deuterium, halo, alkyl, haloalkyl or hydroxyalkyl;
  • R 7 is hydrogen, deuterium or alkyl
  • each W is independently CR 8 or N;
  • R 8 is hydrogen, deuterium, halo or alkyl
  • ring A is a monocyclic, bicyclic or tricyclic aryl, heteroaryl or heterocyclyl optionally substituted with one to four substituents selected from Q 2 ;
  • W 1 is N or C
  • W 2 is N, NR 9a or CR 9b ;
  • W 3 is N, NR 10a or CR 10b ;
  • W 4 is N, NR l la or CR l lb ;
  • R 9a , R 9b , R 10a , R 10b , R l la andR l lb are selected as follows:
  • R 9a , R 10a andR l la are each independently hydrogen or alkyl and R 9b , R 10b andR llb are each independently hydrogen, deuterium, oxo, hydroxyl, halo or alkyl; or ii) R 9a and R 10b , R 9b and R 10b , R 9b and R 10a , R 10b and R lla , R 10a and R l lb or R 10b and R l lb together with the atoms to which they are attached form an aryl, heteroaryl or heterocyclyl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 2 ; and the remainder of R 9a , R 10a and R lla are each independently hydrogen, deuterium or alkyl; and the remainder of R 9b , R 10b and R l lb are each independently hydrogen, deuterium, halo or alkyl; or
  • each Q 2 is independently halo, deuterium, cyano, oxo, thioxo, alkyl, haloalkyl, haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -R u OR x , -R u OR u OR x ,-R u OR u OR x ,-R u OR u OR x ,-R u OR u OR x ,-R u OR u N(R y )(R z ), - R u N(R y )(R z ), -R U SR X , -R U C(J)R X , -
  • R d is hydrogen or alkyl
  • each R u is independently alkylene, alkenylene or a direct bond
  • R w is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
  • each R x is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
  • cycloalkylalkyl cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or
  • R y and R z together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one or more, in one embodiment, one, two or three Q 7 groups; each Q 7 is independently selected from halo, deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
  • J is O, NR X or S
  • each t is independently an integer from 0-2;
  • n 1 or 2;
  • q is an integer from 0-4,
  • R 3 is hydrogen or alkyl
  • R 4 is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, where R 4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 1 ; each Q 1 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
  • Y is -(CR 5 R 6 ) q -;
  • R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl;
  • ring A is aryl or heteroaryl, optionally substituted with one to four substituents selected from Q 2 ;
  • W 1 is N or C
  • W 2 is N, NR 9a or CR 9b ;
  • W 3 is N, NR 10a or CR 10b ;
  • W 4 is N, NR l la or CR l lb ;
  • R 9a , R 9b , R 10a , R 10b , R l la andR l lb are selected as follows:
  • R 9a , R 10a andR l la are each independently hydrogen or alkyl and R 9b , R 10b andR llb are each independently hydrogen, oxo, hydroxyl, halo or alkyl; or
  • R d is hydrogen or alkyl
  • each R u is independently alkylene or a direct bond
  • R w is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
  • each R x is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
  • cycloalkenylalkyl cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
  • R y and R z are each independently selected from (i) or (ii) below:
  • R y and R z are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
  • R y and R z together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one or more, in one embodiment, one, two or three Q 7 groups; each Q 7 is independently selected from halo, deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
  • n 1 or 2;
  • provided herein are compounds of Formula I wherein ring A is heteroaryl, n is 1 and the other variables are as described elsewhere herein. In certain embodiments, provided herein are compounds of Formula I wherein ring A is heteroaryl, W 1 is N, n is 1 or 2 and the other variables are as described elsewhere herein. In certain embodiments, provided herein are compounds of Formula I wherein ring A is heteroaryl, W 1 is C or N, n is 1 or 2, provided that when W 1 is C, n is 1 and the other variables are as described elsewhere herein.
  • ring A is bicyclic or tricyclic heteroaryl, and the other variables are as described elsewhere herein.
  • R 1 and R 2 are each independently selected from hydrogen, halogen, hydroxyl and alkoxy;
  • R 3 is hydrogen or alkyl
  • R 4 is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, where R 4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 1 ;
  • Y is -(CR 5 R 6 ) q -;
  • R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl;
  • Z is O, S or NR 7 ;
  • R 7 is hydrogen or alkyl
  • each W is independently CR 8 or N;
  • R 8 is hydrogen, haloalkyl or alkyl
  • ring A is aryl or heteroaryl, optionally substituted with one to four substituents selected from Q 2 ;
  • W 1 is N or C;
  • W 2 is N, NR 9a or CR 9b ;
  • W 3 is N, NR 10a or CR 10b ;
  • W 4 is N, NR l la or CR l lb ;
  • R 9a , R 9b , R 10a , R 10b , R l la andR l lb are selected as follows:
  • R 9a , R 10a andR l la are each independently hydrogen or alkyl and R 9b , R 10b andR llb are each independently hydrogen, oxo, hydroxyl, halo or alkyl; or
  • each Q 2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
  • each R u is independently alkylene or a direct bond
  • R w is alkyl
  • each R x is independently hydrogen or alkyl
  • R y and R z are each independently hydrogen or alkyl
  • J is O, NR X or S
  • each t is independently an integer from 0-2;
  • n 1 or 2;
  • the compounds provided herein are selected such that when W is CH; W 1 is N; Z is S; R 1 and R 2 are hydrogen, then ring A is not pyrrolidine.
  • the compounds provided herein are selected such that when W is CH; W 1 is N; Z is S; R 1 and R 2 are hydrogen, then ring A is not 5 -membered heterocyclyl.
  • the compounds provided herein are selected such that when Z is N, one of R 1 and R 2 is methyl and the other of R 1 and R 2 is H, q is 0, and R 3 is pyridine, and W 1 is N, ring A cannot be nitrogen containing heterocyclyl.
  • the compounds provided herein are selected such that when Z is N, one of R 1 and R 2 is methyl and the other of R 1 and R 2 is H, q is 0, and R 3 is pyridine, and W 1 is N, ring A cannot be heterocyclyl.
  • R 1 and R 2 are each independently selected from hydrogen and halogen.
  • R 1 and R 2 are each hydrogen.
  • R 1 is hydrogen and R 2 is halogen.
  • R 1 and R 2 are each halogen.
  • R 1 and R 2 are each independently selected from hydrogen and fluorine.
  • R 1 is alkoxy and R 2 is hydrogen.
  • R 1 is hydroxy and R 2 is hydrogen.
  • R 3 is hydrogen or alkyl. In certain embodiments, R 3 is hydrogen or methyl. In certain embodiments, R 3 is hydrogen.
  • R 4 is cyclohexyl, optionally substituted with hydroxyl.
  • Y is direct bond or -(CR 5 R 6 ) q -; R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl. In certain embodiments, Y is direct bond or -(CR 5 R 6 ) q -; R 5 and R 6 are each independently hydrogen, alkyl or hydroxyalkyl. In certain embodiments, Y is direct bond, -CH 2 -, -CH(CH 3 )- or -CH(CH 2 OH)-.
  • Z is O, S or NH. In certain embodiments, Z is O or S.
  • each W is independently CR 8 or N; and R 8 is hydrogen, halo or alkyl. In certain embodiments, each W is CR 8 ; and R 8 is hydrogen or alkyl. In certain embodiments, each W is CH.
  • ring A is aryl or heteroaryl, optionally substituted with one or two substituents selected from Q 2 ; where Q 2 is heteroaryl,
  • each R u is independently alkylene or a direct bond;
  • R y and R z are each independently hydrogen or alkyl
  • ring A is heteroaryl, optionally substituted with one or two substituents selected from Q 2 ; where Q 2 is heteroaryl,
  • each R u is independently alkylene or a direct bond;
  • each R x is independently hydrogen or alkyl
  • R y and R z are each independently hydrogen or alkyl
  • J is O, NR X or S.
  • stereoisomers mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein:
  • R 3 is hydrogen or alkyl
  • R 4 is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, where R 4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 1 ;
  • each Q 1 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
  • Y is -(CR 5 R 6 ) q -;
  • R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl;
  • Z is O, S or NR 7 ;
  • R 7 is hydrogen or alkyl
  • R 8 is hydrogen, halo, haloalkyl or alkyl
  • ring A is a bicyclic or tricyclic heteroaryl or heterocyclyl optionally substituted with one to four substituents selected from Q 2 ;
  • W 1 is N or C
  • W 2 is N, NR 9a or CR 9b ;
  • W 3 is N, NR 10a or CR 10b ;
  • W 4 is N, NR l la or CR l lb ;
  • R 9a , R 9b , R 10a , R 10b , R l la andR l lb are selected as follows:
  • R 9b , R 10b and R l lb are each independently hydrogen, halo or alkyl; or
  • each Q 2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,
  • R d is hydrogen or alkyl
  • each R u is independently alkylene, alkenylene or a direct bond
  • R w is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
  • each R x is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
  • R y and R z are each independently selected from (i) or (ii) below:
  • R y and R z are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
  • cycloalkylalkyl cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or
  • R y and R z together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one or more, in one embodiment, one, two or three Q 7 groups; each Q 7 is independently selected from halo, deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
  • cycloalkenylalkyl aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;
  • J is O, NR X or S
  • each t is independently an integer from 0-2;
  • n 1 or 2;
  • q is an integer from 0-4,
  • W 1 is N. In certain embodiments, W 1 is C.
  • W 2 is N or CR 9b , where R 9b is hydrogen oxo, hydroxyl or alkyl.
  • W 3 is N or CR 10b , where R 10b is hydrogen or alkyl.
  • W 4 is N or CR l lb , where R l lb is hydrogen or alkyl.
  • W 2 is CR 9b ;
  • W 3 is CR 10b ;
  • W 4 is N or CR l lb ; where R 9b and R 10b together with the carbon atoms on which they are substituted form an aryl or heteroaryl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 2 ;
  • R l lb is hydrogen or alkyl;
  • each Q 2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
  • each R u is independently alkylene or a direct bond
  • R w is alkyl
  • each R x is independently hydrogen or alkyl
  • R y and R z are each independently hydrogen or alkyl
  • J is O, NR X or S
  • each t is independently an integer from 0-2.
  • W 2 is CR 9b ;
  • W 3 is CR 10b ;
  • W 4 is N; where R 9b and R 10b together with the carbon atoms on which they are substituted form an aryl or heteroaryl ring, optionally substituted with one or two groups selected from Q 2 , where Q 2 is as defined elsewhere herein.
  • R w is alkyl
  • each R x is independently hydrogen or alkyl
  • R y and R z are each independently hydrogen or alkyl
  • J is O, NR X or S
  • each t is independently an integer from 0-2.
  • n is 1 or 2. In certain embodiments, n is 1. In certain embodiments, n is 2.
  • q is an integer from 0-4. In certain embodiments, q is 0-3. In certain embodiments, q is 0-2. In certain embodiments, q is 0, 1 or 2. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2.
  • R 1 and R 2 are each independently selected from hydrogen, alkoxy and halogen
  • R 3 is hydrogen or alkyl
  • R 4 is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R 4 is optionally substituted with one or more, in one embodiment, one to three, in another
  • R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl;
  • Z is O, S, or NR 7 ;
  • R 7 is hydrogen or alkyl
  • each W is independently CR 8 or N;
  • R 8 is hydrogen, haloalkyl or alkyl; ring A is aryl or heteroaryl;
  • W 1 is N or C
  • W 2 is N, NR 9a or CR 9b ;
  • W 4 is N, NR l la or CR l lb ;
  • R 9a , R 9b , R 10a , R 10b , R l la andR l lb are selected as follows:
  • R 9a , R 10a andR l la are each independently hydrogen or alkyl; and R 9b , R 10b andR llb are each independently hydrogen, oxo, hydroxyl, halo or alkyl; or
  • each Q 2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
  • each R u is independently alkylene or a direct bond
  • R y and R z are each independently hydrogen or alkyl
  • J is O, NR X or S
  • n 1 ;
  • q is an integer from 0-2.
  • R 1 and R 2 are each independently selected from hydrogen, alkoxy and halogen
  • R 4 is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, where R 4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 1 ;
  • Y is -(CR 5 R 6 ) q -;
  • R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl;
  • Z is O, S, or NR 7 ;
  • each W is independently CR 8 or N;
  • R 8 is hydrogen, haloalkyl or alkyl
  • ring A is aryl or heteroaryl, optionally substituted with one to four substituents selected from Q 2 ;
  • W 1 is N or C
  • W 2 is N, NR 9a or CR 9b ;
  • W 3 is N, NR 10a or CR 10b ;
  • W 4 is N, NR l la or CR l lb ;
  • R 9a , R 9b , R 10a , R 10b , R l la andR l lb are selected as follows:
  • R 9a , R 10a andR l la are each independently hydrogen or alkyl and R 9b , R 10b andR llb are each independently hydrogen or Q 2 ; or
  • R 9a and R 10b R 9a and R 10a , R 9b and R 10b , R 9b and R 10a , R 10a and R l la , R 10b and R l la , R 10a and R l lb or R 10b and R l lb together with the atoms to which they are attached form an aryl or heteroaryl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 2 ; the remainder of R 9a or R l la is hydrogen or alkyl; and the remainder of R 9b or R l lb is independently hydrogen or Q 2 ;
  • each Q 2 is independently halo, deuterium, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -R u OR x , -R u OR u OR x ,-R u OR u OR x ,-R u OR u OR x ,-R u OR u N(R y )(R z ), - R u N(R y )(R z ), -R U SR X , -R U C(J)R X , -R u C(J)OR x ,
  • each R d is independently hydrogen or alkyl
  • each R u is independently alkylene, alkenylene or a direct bond
  • R w is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
  • each R x is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
  • R y and R z are each independently selected from (i) or (ii) below: (i) R y and R z are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or
  • R y and R z together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one or more, in one embodiment, one, two or three Q 7 groups; each Q 7 is independently selected from halo, deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
  • J is O, NR X or S
  • each t is independently an integer from 0-2;
  • q is an integer from 0-2;
  • compounds of Formula II wherein ring A is heteroaryl optionally substituted with one to four substituents selected from Q 2 ; n is 1 and the other variables are as described elsewhere herein.
  • R 1 and R 2 are each independently selected from hydrogen, alkoxy and halogen;
  • R 3 is hydrogen or alkyl
  • R 4 is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, where R 4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 1 ;
  • Y is -(CR 5 R 6 ) q -;
  • R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl;
  • R 7 is hydrogen or alkyl
  • each W is independently CR 8 or N;
  • R 8 is hydrogen, halo, haloalkyl or alkyl
  • ring A is aryl or heteroaryl, optionally substituted with one to four substituents selected from Q 2 ;
  • W 1 is N or C
  • W 2 is N, NR 9a or CR 9b ;
  • W 3 is N, NR 10a or CR 10b ;
  • W 4 is N, NR l la or CR l lb ;
  • R 9a , R 9b , R 10a , R 10b , R l la andR l lb are selected as follows:
  • R 9a , R 10a andR l la are each independently hydrogen or alkyl and R 9b , R 10b andR llb are each independently hydrogen, oxo, hydroxyl, halo or alkyl; or
  • R 9a and R 10b R 9a and R 10a , R 9b and R 10b , R 9b and R 10a , R 10a and R l la , R 10b and R l la , R 10a and R l lb or R 10b and R l lb together with the atoms to which they are attached form an aryl or heteroaryl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 2 ; the remainder of R 9a , R 10a and R l la are each independently hydrogen or alkyl; the remainder of R 9b R 10b and R l lb are each independently hydrogen, halo or alkyl;
  • each Q 2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
  • each R u is independently alkylene or a direct bond
  • R w is alkyl
  • each R x is independently hydrogen or alkyl
  • R y and R z are each independently hydrogen or alkyl
  • J is O, NR X or S
  • each t is independently an integer from 0-2;
  • q is an integer from 0-2.
  • ring A is heteroaryl optionally substituted with one to four substituents selected from Q 2 and the other variables are as described elsewhere herein.
  • ring A is bicyclic or tricyclic heteroaryl, and the other variables are as described elsewhere herein.
  • stereoisomers mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein:
  • R 1 and R 2 are each independently selected from hydrogen, alkoxy and halogen
  • R 3 is hydrogen or alkyl
  • R 4 is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, where R 4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 1 ;
  • Y is -(CR 5 R 6 ) q -;
  • R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl;
  • Z is O, S, or NR 7 ;
  • R 7 is hydrogen or alkyl
  • each W is independently CR 8 or N;
  • R 8 is hydrogen, halo, haloalkyl or alkyl
  • ring A is heteroaryl or heterocyclyl, optionally substituted with one to four substituents selected from Q 2 ;
  • W 1 is N or C
  • W 2 is N, NR 9a or CR 9b ;
  • W 4 is N, NR l la or CR l lb ;
  • R 9a , R 9b , R 10a , R 10b , R l la andR l lb are selected as follows:
  • R 9a , R 10a andR l la are each independently hydrogen or alkyl and R 9b , R 10b andR llb are each independently hydrogen, oxo, hydroxyl, halo or alkyl; or
  • R 9a and R 10b R 9a and R 10a , R 9b and R 10b , R 9b and R 10a , R 10a and R l la , R 10b and R l la , R 10a and R l lb or R 10b and R l lb together with the atoms to which they are attached form an aryl, heteroaryl or heterocyclyl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 2 ; the remainder of R 9a , R 10a and R l la are each independently hydrogen or alkyl; the remainder of R 9b R 10b and R l lb are each independently hydrogen, halo or alkyl; or
  • each R x is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
  • R y and R z are each independently selected from (i) or (ii) below:
  • R y and R z are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
  • cycloalkylalkyl cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or
  • cycloalkenylalkyl aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;
  • J is O, NR X or S
  • each t is independently an integer from 0-2;
  • stereoisomers mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein:
  • R 1 and R 2 are each independently selected from hydrogen, alkoxy and halogen
  • R 3 is hydrogen or alkyl
  • R 4 is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, where R 4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 1 ;
  • Y is -(CR 5 R 6 ) q -;
  • R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl;
  • Z is O, S, or NR 7 ;
  • R 7 is hydrogen or alkyl
  • each W is independently CR 8 or N;
  • R 8 is hydrogen, halo, haloalkyl or alkyl
  • ring A is bicyclic heteroaryl or heterocyclyl, optionally substituted with one to four substituents selected from Q 2 ;
  • W 1 is N or C
  • W 2 is N, NR 9a or CR 9b ;
  • W 3 is CR 10b ;
  • R 9a , R 9b , and R 10b are selected as follows:
  • R 9a and R 10b or R 9b and R 10b together with the atoms to which they are attached, form an aryl, heteroaryl or heterocyclyl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 2 ; the remainder of R 9a and R 10b is hydrogen or alkyl;
  • each Q 2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,
  • each R u is independently alkylene, alkenylene or a direct bond
  • R w is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
  • each R x is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
  • R y and R z are each independently selected from (i) or (ii) below:
  • R y and R z are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
  • cycloalkylalkyl cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or
  • R y and R z together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one or more, in one embodiment, one, two or three Q 7 groups; each Q 7 is independently selected from halo, deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
  • cycloalkenylalkyl aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;
  • J is O, NR X or S
  • each t is independently an integer from 0-2;
  • q is an integer from 0-2.
  • q is 0; and the other variables are as described elsewhere herein.
  • stereoisomers mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein:
  • R 1 and R 2 are each independently selected from hydrogen, halogen, alkoxy and hydroxyl;
  • R 3 is hydrogen or alkyl
  • R 4 is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R 4 is optionally substituted with one or more, in one embodiment, one to three, in another
  • each Q 1 is independently deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,
  • Y is -(CR 5 R 6 ) q -;
  • R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl;
  • Z is O, S or NH
  • each W is independently CR 8 or N;
  • R 8 is hydrogen, halo, haloalkyl or alkyl
  • ring A is heteroaryl or heterocyclyl, optionally substituted with one to four substituents selected from Q 2 ;
  • W 2 is N or CR 9b ;
  • W 3 is N or CR 10b ;
  • W 4 is N or CR llb ;
  • R 9b , R 10b andR l lb are selected as follows:
  • R 9b , R 10b andR l lb are each independently hydrogen or Q 2 ; or ii) R 9b and R 10b or R 10b and R l lb together with the atoms to which they are attached form an aryl or heteroaryl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 2 ; and the remainder of R 9b , R 10b and R llb is hydrogen or Q 2 ;
  • each Q 2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,
  • R d is hydrogen or alkyl
  • each R u is independently alkylene, alkenylene or a direct bond
  • R w is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
  • each R x is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
  • R y and R z are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
  • cycloalkylalkyl cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or
  • R y and R z together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one or more, in one embodiment, one, two or three Q 7 groups; each Q 7 is independently selected from halo, deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
  • cycloalkenylalkyl aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;
  • J is O, NR X or S
  • q is an integer from 0-4.
  • stereoisomers mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein:
  • R 1 and R 2 are each independently selected from hydrogen, halogen, alkoxy and hydroxyl;
  • R 4 is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R 4 is optionally substituted with one or more, in one embodiment, one to three, in another
  • Y is -(CR 5 R 6 ) q -;
  • R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl;
  • Z is O, S or NH
  • each W is independently CR 8 or N;
  • R 8 is hydrogen, halo, haloalkyl or alkyl
  • ring A is heteroaryl, optionally substituted with one to four substituents selected from Q 2 ;
  • W 3 is N or CR 10b ;
  • W 4 is N or CR llb ;
  • R 9b , R 10b andR l lb are selected as follows:
  • R 9b , R 10b andR l lb are each independently hydrogen, oxo, hydroxyl, halo or alkyl; or
  • R 9b and R 10b or R 10b and R l lb together with the atoms to which they are attached form an aryl or heteroaryl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 2 ; and the remainder of R 9b , R 10b and R llb is hydrogen, halo or alkyl;
  • each Q 2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
  • each R u is independently alkylene or a direct bond
  • R w is alkyl
  • each R x is independently hydrogen or alkyl
  • J is O, NR X or S
  • each t is independently an integer from 0-2;
  • n 1 or 2;
  • q is an integer from 0-4.
  • provided herein are compounds of Formula III wherein ring A is heteroaryl and the other variables are as described elsewhere herein. In certain embodiments, provided herein are compounds of Formula III, wherein ring A is bicyclic or tricyclic heteroaryl, and the other variables are as described elsewhere herein.
  • R 1 and R 2 are each independently selected from hydrogen or halogen;
  • R 3 is hydrogen or alkyl;
  • Y is -(CR 5 R 6 ) q -;
  • R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl;
  • Z is O, S, or NH
  • each W is independently CR 8 or N;
  • R 8 is hydrogen, halo, haloalkyl or alkyl
  • ring A is heteroaryl optionally substituted with one to four substituents selected from Q 2 ;
  • W 2 is N or CR 9b ;
  • W 3 is N or CR 10b ;
  • W 4 is N or CR llb ;
  • R 9b , R 10b andR l lb are selected as follows:
  • each Q 2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
  • each R u is independently alkylene or a direct bond
  • R w is alkyl
  • each R x is independently hydrogen or alkyl
  • R y and R z are each independently hydrogen or alkyl
  • J is O, NR X or S
  • each t is independently an integer from 0-2; n is 1 or 2; and
  • q is an integer from 0-2.
  • R 4 is cycloalkyl, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 1 ;
  • Y is -(CR 5 R 6 ) q -;
  • R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl;
  • R 8 is hydrogen, halo, haloalkyl or alkyl
  • ring A is heteroaryl optionally substituted with one to four substituents selected from Q 2 ;
  • W 3 is N or CR 10b ;
  • W 4 is N or CR llb ;
  • R 9b , R 10b andR l lb are selected as follows:
  • each Q 2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
  • R w is alkyl
  • R y and R z are each independently hydrogen or alkyl
  • J is O, NR X or S
  • each t is independently an integer from 0-2;
  • n 1 or 2;
  • q is an integer from 0-2.
  • stereoisomers mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein:
  • R 1 and R 2 are each independently selected from hydrogen, halogen, alkoxy and hydroxyl;
  • R 3 is hydrogen or alkyl
  • R 4 is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R 4 is optionally substituted with one or more, in one embodiment, one to three, in another
  • each Q 1 is independently deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,
  • Y is -(CR 5 R 6 ) q -;
  • R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl;
  • Z is O, S or NH
  • each W is independently CR 8 or N;
  • R 8 is hydrogen, halo, haloalkyl or alkyl
  • ring A is heteroaryl optionally substituted with one to four substituents selected from Q 2 ;
  • W 2 is N or CR 9b ;
  • W 4 is N or CR llb ;
  • each Q 2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,
  • R d is hydrogen or alkyl
  • each R u is independently alkylene, alkenylene or a direct bond
  • R w is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; each R x is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
  • R y and R z are each independently selected from (i) or (ii) below:
  • R y and R z are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
  • cycloalkylalkyl cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or
  • R y and R z together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one or more, in one embodiment, one, two or three Q 7 groups; each Q 7 is independently selected from halo, deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
  • cycloalkenylalkyl aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;
  • each t is independently an integer from 0-2;
  • q is an integer from 0-4.
  • stereoisomers mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein:
  • R 1 and R 2 are each independently selected from hydrogen, halogen, alkoxy and hydroxyl;
  • R 4 is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R 4 is optionally substituted with one or more, in one embodiment, one to three, in another
  • Y is -(CR 5 R 6 ) q -;
  • R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl;
  • Z is O, S or NH
  • each W is independently CR 8 or N;
  • R 8 is hydrogen, halo, haloalkyl or alkyl
  • ring A is heteroaryl or heterocyclyl optionally substituted with one to four substituents selected from Q 2 ;
  • W 3 is N or CR 10b ;
  • W 4 is N or CR llb ;
  • R 9b , R 10b andR l lb are selected as follows:
  • R 9b , R 10b andR l lb are each independently hydrogen, oxo, hydroxyl, halo or alkyl; or
  • R 9b and R 10b or R 10b and R l lb together with the atoms to which they are attached form an aryl or heteroaryl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 2 ; and the remainder of R 9b , R 10b and R llb is hydrogen, halo or alkyl;
  • each Q 2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
  • each R u is independently alkylene, alkenylene or a direct bond
  • R w is alkyl
  • each R x is independently hydrogen or alkyl
  • R y and R z are each independently hydrogen or alkyl
  • J is O, NR X or S
  • R 4 is cycloalkyl, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 1 ;
  • each Q 1 is independently deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,
  • R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl;
  • Z is O, S, or NH
  • R 8 is hydrogen, halo, haloalkyl or alkyl
  • ring A is heteroaryl optionally substituted with one to four substituents selected from Q 2 ;
  • W 3 is N or CR 10b ;
  • W 4 is N or CR llb ;
  • R 9b , R 10b andR l lb are selected as follows:
  • R 9b , R 10b andR l lb are each independently hydrogen, oxo, hydroxyl, halo or alkyl; or
  • R 9b and R 10b or R 10b and R l lb together with the atoms to which they are attached, form an aryl or heteroaryl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 2 ; and the remainder of R 9b , R 10b and R llb is hydrogen, halo or alkyl;
  • each Q 2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,
  • R d is hydrogen or alkyl
  • each R u is independently alkylene, alkenylene or a direct bond
  • R w is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
  • each R x is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
  • R y and R z are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
  • cycloalkylalkyl cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or
  • R y and R z together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one or more, in one embodiment, one, two or three Q groups; each Q is independently selected from halo, deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
  • cycloalkenylalkyl aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;
  • each t is independently an integer from 0-2;
  • n 1 or 2;
  • n 1 and the other variables are as described elsewhere herein.
  • R 4 is cycloalkyl, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 1 ;
  • Y is -(CR 5 R 6 ) q -;
  • Z is O, S, or NH
  • W 2 is N or CR 9b ;
  • W 4 is N or CR llb ;
  • R 9b and R 10b or R 10b and R l lb together with the atoms to which they are attached, form an aryl or heteroaryl ring, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 2 ; and the remainder of R 9b , R 10b and R llb is hydrogen, halo or alkyl;
  • each R u is independently alkylene or a direct bond
  • R w is alkyl
  • J is O, NR X or S
  • R 4 is cycloalkyl, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 1 ;
  • Z is O, S, or NH
  • each W is independently CR 8 or N;
  • W 2 is N or CR 9b ;
  • W 3 is N or CR 10b ;
  • W 4 is N or CR llb ;
  • R 9b and R 10b together with the atoms to which they are attached, form an aryl or heteroaryl ring, optionally substituted with one or two groups selected from
  • each Q 2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
  • each R u is independently alkylene or a direct bond
  • R w is alkyl
  • each R x is independently hydrogen or alkyl
  • R y and R z are each independently hydrogen or alkyl
  • J is O, NR X or S; each t is independently an integer from 0-2;
  • R l lb is hydrogen
  • n 1 or 2;
  • q is an integer from 0-2.
  • R 1 and R 2 are each independently selected from hydrogen or halogen;
  • R 3 is hydrogen or alkyl;
  • R 4 is cycloalkyl, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 1 ;
  • Y is -(CR 5 R 6 ) q -;
  • R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl;
  • Z is O, S, or NH
  • each W is independently CR 8 or N;
  • R 8 is hydrogen, halo, haloalkyl or alkyl
  • ring A is heteroaryl, optionally substituted with one to four substituents selected from Q 2 ;
  • W 2 is N or CR 9b ;
  • W 3 is N or CR 10b ;
  • W 4 is N or CR llb ;
  • R 9b and R 10b together with the atoms to which they are attached, form an aryl or heteroaryl ring, optionally substituted with one or two groups selected from
  • each Q 2 is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
  • each R u is independently alkylene or a direct bond
  • R w is alkyl
  • each R x is independently hydrogen or alkyl
  • R y and R z are each independently hydrogen or alkyl
  • J is O, NR X or S
  • each t is independently an integer from 0-2;
  • R l lb is hydrogen
  • n 1 or 2;
  • q is an integer from 0-2.
  • R 1 and R 2 are each independently selected from hydrogen or halogen;
  • R 3 is hydrogen or alkyl;
  • R 4 is cycloalkyl, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 1 ;
  • Y is -(CR 5 R 6 ) q -;
  • R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl;
  • Z is O, S, or NH
  • each W is independently CR 8 or N;
  • R 8 is hydrogen, halo, haloalkyl or alkyl
  • ring A is heteroaryl, optionally substituted with one to four substituents selected from Q 2 ;
  • W 2 is N or CR 9b ;
  • W 3 is N or CR 10b ;
  • W 4 is N or CR llb ;
  • R 9b and R 10b together with the carbon atoms to which they are attached, form an aryl or heteroaryl ring, optionally substituted with one or two groups Q 2 , each Q 2 is independently halo, cyano, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclyl, -R u OR x , -R u N(R y )(R z ), -R U SR X , -R U C(J)R X , - R u C(J)OR x , -R u C(J)N(R y )(R z ), -R u C(J)N(R y )OR x , -R u S(0),R w , -R U N(R X )C(J)R X , - R u N(R x ,
  • R l lb is hydrogen or Q 2 ;
  • each R u is independently alkylene or a direct bond
  • R w is alkyl
  • each R x is independently hydrogen or alkyl
  • R y and R z are each independently hydrogen or alkyl
  • J is O, NR X or S
  • each t is independently an integer from 0-2;
  • q is an integer from 0-2.
  • R 1 and R 2 are each independently selected from hydrogen or halogen;
  • R 3 is hydrogen or alkyl;
  • R 4 is cycloalkyl, optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 1 ;
  • Y is -(CR 5 R 6 ) q -;
  • R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl;
  • Z is O, S, or NH
  • each W is independently CR 8 or N;
  • R 8 is hydrogen, halo, haloalkyl or alkyl; ring A is heteroaryl, optionally substituted with one to four substituents selected from Q 2 ;
  • W 2 is N or CR 9b ;
  • W 3 is N or CR 10b ;
  • W 4 is N or CR llb ;
  • R 9b and R 10b together with the carbon atoms to which they are attached, form an aryl or heteroaryl ring, optionally substituted with one or two groups Q 2 , each Q 2 is independently halo, cyano, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclyl, -R u OR x , -R u N(R y )(R z ), -R U SR X , -R U C(J)R X , - R u C(J)OR x , -R u C(J)N(R y )(R z ), -R u C(J)N(R y )OR x , -R u S(0),R w , -R U N(R X )C(J)R X , - R u N(R x ,
  • each R u is independently alkylene or a direct bond
  • R w is alkyl
  • each R x is independently hydrogen or alkyl
  • R y and R z are each independently hydrogen or alkyl
  • J is O, NR X or S
  • each t is independently an integer from 0-2;
  • q is an integer from 0-2.
  • R 1 and R 2 are each independently selected from hydrogen, halogen, and hydroxyl
  • R 3 is hydrogen or alkyl
  • R 4 is cycloalkyl, where R 4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 1 ;
  • Y is -(CR 5 R 6 ) q -;
  • R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl;
  • Z is O, S, or NH
  • each W is independently CR 8 or N;
  • R 8 is hydrogen, halo, haloalkyl or alkyl
  • ring A is heteroaryl, optionally substituted with one to four substituents selected from Q 2 ;
  • W 2 is N or CR 9b ;
  • W 3 is N or CR 10b ;
  • W 4 is N or CR llb ;
  • R 9b , R 10b andR l lb are selected as follows:
  • R 9b , R 10b andR l lb are each independently hydrogen or Q 2 ; or ii) R 9b and R 10b or R 10b and R l lb , together with the atoms on which they are substituted form an aryl, heteroaryl ring, optionally substituted with one or two groups selected from Q 2 ; and the remainder of R 9b orR l lb is hydrogen or Q 2 ;
  • each Q 2 is hydrogen, halo, alkoxy, tetrazole or pyrazole, where the tetrazole and pyrazole rings are optionally substituted with one or more alkyl;
  • each R u is independently alkylene or a direct bond
  • R w is alkyl
  • each R x is independently hydrogen or alkyl
  • n 1 or 2;
  • R 3 is hydrogen or alkyl
  • R 4 is cycloalkyl, where R 4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 1 ;
  • R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl;
  • each W is independently CR 8 or N;
  • W 3 is N or CR 10b ;
  • W 4 is N or CR llb ;
  • R 9b , R 10b andR l lb are selected as follows:
  • R 9b , R 10b andR l lb are each independently hydrogen, oxo, hydroxyl, halo or alkyl; or
  • R 9b and R 10b or R 10b and R l lb together with the atoms on which they are substituted form an aryl, heteroaryl ring, optionally substituted with one or two groups selected from Q 2 ; and the remainder of R 9b , R 10b or R llb is hydrogen or alkyl;
  • each Q 2 is hydrogen, halo, alkoxy, tetrazole or pyrazole, where the tetrazole and pyrazole rings are optionally substituted with one or more alkyl;
  • R w is alkyl
  • each R x is independently hydrogen or alkyl
  • R y and R z are each independently hydrogen or alkyl
  • J is O, NR X or S
  • each t is independently an integer from 0-2;
  • n 1 or 2;
  • q is an integer from 0-4.
  • each Q 1 is independently deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,
  • W 1 is N or C
  • W 2 is N or CR 9b ;
  • R 9b is hydrogen or Q 2 ;
  • W 5 is N or CR 13 ;
  • R l lb and R 13 are each independently hydrogen or Q ;
  • Q 5 and Q 6 are each independently hydrogen, deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,
  • heteroaralkyl heterocyclyl, heterocyclylalkyl, -R u OR x , - R u OR u OR x , -R u OR u N(R y )(R z ), -R u N(R y )(R z ), -R U SR X ,
  • R w is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
  • each R x is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
  • cycloalkylalkyl cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or
  • R y and R z together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one or more, in one embodiment, one, two or three Q 7 groups; each Q 7 is independently selected from halo, deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
  • cycloalkenylalkyl aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;
  • J is O, NR X or S
  • each t is independently an integer from 0-2;
  • q is an integer from 0-4.
  • provided herein are compounds of Formula IV wherein R 1 and R 2 are both hydrogen.
  • provided herein are compounds of Formula IV wherein R 9b and R l lb are each independently hydrogen, alkyl or haloalkyl and the other variables are as described elsewhere herein.
  • R 4 is cycloalkyl.
  • R 9b andR l lb are each independently hydrogen, halo or alkyl and the other variables are as described elsewhere herein.
  • R 1 and R 2 are each independently selected from hydrogen or halogen;
  • R 3 is hydrogen or alkyl;
  • R 4 is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, where R 4 is optionally substituted with one or more, in one embodiment, one to three, in another embodiment, one, two or three groups selected from Q 1 ;
  • Y is -(CR 5 R 6 ) q -;
  • R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl;
  • Z is O, S, or NH
  • each W is independently CR 8 or N;
  • W 2 is N or CR 9b ;
  • R 9b is hydrogen or alkyl
  • W 4 is N or CR llb ;
  • R l lb is hydrogen, halo or alkyl
  • W 5 is N or CR 13 ;
  • each R u is independently alkylene or a direct bond
  • R w is alkyl
  • each R x is independently hydrogen or alkyl
  • R y and R z are each independently hydrogen or alkyl
  • each t is independently an integer from 0-2;
  • Y is -(CR 5 R 6 ) q -;
  • R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl;
  • W 2 is N or CR 9b ;
  • R 9b is hydrogen or alkyl
  • R l lb is hydrogen or Q 2 ;
  • Q 2 is halo, deuterium, cyano, oxo, thioxo, alkyl, haloalkyl, haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
  • each R x is independently hydrogen or alkyl
  • q is an integer from 0-4.
  • stereoisomers mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein:
  • R 1 and R 2 are each independently selected from hydrogen or halogen;
  • R 3 is hydrogen or alkyl;
  • Y is -(CR 5 R 6 ) q -;
  • R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl;
  • Z is O, S, or NH
  • R 8 is hydrogen, halo, haloalkyl or alkyl
  • W 1 is N or C
  • R 9b is hydrogen or alkyl
  • W 4 is N or CR llb ;
  • R l lb is hydrogen, halo or alkyl;
  • W 5 is N or CR 13 ;
  • R 13 is hydrogen, halo or alkyl
  • Q 5 and Q 6 are each independently hydrogen, deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,
  • each R u is independently alkylene, alkenylene or a direct bond
  • R w is alkyl
  • each R x is independently hydrogen or alkyl
  • R y and R z are each independently hydrogen or alkyl
  • J is O, NR X or S
  • each t is independently an integer from 0-2;
  • q is an integer from 0-4.
  • R l lb and R 13 are each independently hydrogen, halo or alkyl and the other variables are as described elsewhere herein.
  • stereoisomers mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein the variables are as described elsewhere herein.
  • provided herein are compounds of Formula V or pharmaceutically acceptable salts, solvates, hydrates, clathrates, single stereoisomers, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein R 1 and R 2 are each independently selected from hydrogen or halogen;
  • R 3 is hydrogen or alkyl
  • R 4 is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R 4 is optionally substituted with one or more, in one embodiment, one to three, in another
  • each Q 1 is independently deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,
  • Y is -(CR 5 R 6 ) q -;
  • R 5 andR 6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl;
  • Z is O, S, or NH
  • each W is independently CR 8 or N;
  • R 8 is hydrogen, halo, haloalkyl or alkyl
  • W 4 is N or CR llb ;
  • W 5 is N or CR 13 ;
  • R l lb and R 13 are each independently hydrogen or Q ;
  • Q 2 is halo, deuterium, cyano, oxo, thioxo, alkyl, haloalkyl, haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,
  • Q 5 and Q 6 are each independently hydrogen, deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,
PCT/US2012/059983 2011-10-14 2012-10-12 Heterocyclic compounds and methods of use thereof WO2013056070A2 (en)

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IN3597CHN2014 IN2014CN03597A (pt) 2011-10-14 2012-10-12
NZ623274A NZ623274B2 (en) 2011-10-14 2012-10-12 Heterocyclic compounds and use thereof as modulators of type iii receptor tyrosine kinases
EP12780613.1A EP2766359B9 (en) 2011-10-14 2012-10-12 Heterocyclic compounds and use thereof as modulators of type iii receptor tyrosine kinases
CA2851155A CA2851155C (en) 2011-10-14 2012-10-12 Heterocyclic compounds and methods of use thereof
KR1020147012791A KR102066297B1 (ko) 2011-10-14 2012-10-12 헤테로사이클릭 화합물 및 이의 유형 3 수용체 티로신 키나아제의 조절인자로서의 용도
MX2014004252A MX368081B (es) 2011-10-14 2012-10-12 Compuestos heterociclicos y uso de los mismos como moduladores del receptor de tirosina cinasas tipo iii.
AU2012322095A AU2012322095B2 (en) 2011-10-14 2012-10-12 Heterocyclic compounds and use thereof as modulators of type III receptor tyrosine kinases
SI201230628A SI2766359T1 (sl) 2011-10-14 2012-10-12 Heterociklične spojine in njihova uporaba kot modulatorjev receptorja tirozin kinaze tipa III
DK12780613.1T DK2766359T5 (en) 2011-10-14 2012-10-12 Heterocyclic compounds and their use as modulators of type III receptor tyrosine kinases
RU2014119244A RU2648997C2 (ru) 2011-10-14 2012-10-12 Гетероциклические соединения и способы их использования
CN201280062194.7A CN104066730B (zh) 2011-10-14 2012-10-12 杂环化合物及其作为iii型受体酪氨酸激酶调节剂的用途
BR112014009006A BR112014009006B8 (pt) 2011-10-14 2012-10-12 Compostos heterocíclicos e métodos de uso dos mesmos
SG11201401236XA SG11201401236XA (en) 2011-10-14 2012-10-12 Heterocyclic compounds and use thereof as modulators of type iii receptor tyrosine kinases
RS20160502A RS54936B1 (sr) 2011-10-14 2012-10-12 Heterociklična jedinjenja i njihova upotreba kao modulatora receptora tirozin kinaza tipa iii
ES12780613.1T ES2586527T3 (es) 2011-10-14 2012-10-12 Compuestos heterocíclicos y uso de los mismos como moduladores del receptor de tirosina quinasas de tipo III
JP2014535928A JP6162130B2 (ja) 2011-10-14 2012-10-12 Ｉｉｉ型受容体チロシンキナーゼの調節因子としての複素環式化合物及びその使用
IL231927A IL231927A (en) 2011-10-14 2014-04-03 The heterocyclic compounds and their use as a tyrosine kinase receptor modulator III
ZA2014/02549A ZA201402549B (en) 2011-10-14 2014-04-08 Heterocyclic compounds and use thereof as modulators of type iii receptor tyrosine kinases
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015035167A1 (en) * 2013-09-06 2015-03-12 Lexicon Pharmaceuticals, Inc. IMIDAZO[1,2-b]PYRIDAZINE-BASED COMPOUNDS, COMPOSITIONS COMPRISING THEM, AND METHODS OF THEIR USE
US20150197516A1 (en) * 2012-08-22 2015-07-16 Merck Sharp & Dohme Corp. a corporation, a subsidiary of Merck & Co., Inc. Novel benzimidazole tetrahydropyran derivatives
WO2018025168A1 (en) 2016-08-03 2018-02-08 Pfizer Inc. Heteroaryl sulfone-based conjugation handles, methods for their preparation, and their use in synthesizing antibody drug conjugates
WO2018086609A1 (zh) 2016-11-14 2018-05-17 江苏恒瑞医药股份有限公司 3,4-二吡啶基吡唑类衍生物、其制备方法及其在医药上的应用
WO2018136935A1 (en) 2017-01-23 2018-07-26 University Of Hawaii 2-arylsulfonamido-n-arylacetamide derivatized stat3 inhibitors
CN108602821A (zh) * 2015-12-14 2018-09-28 齐尼思表观遗传学有限公司 1h-咪唑并[4,5-b]吡啶基和2-氧代-2,3-二氢-1h-咪唑并[4,5-b]吡啶基杂环bet溴结构域抑制剂
WO2019113469A1 (en) 2017-12-07 2019-06-13 The Regents Of The University Of Michigan Nsd family inhibitors and methods of treatment therewith
US11274108B2 (en) 2015-07-20 2022-03-15 Genzyme Corporation Colony stimulating factor-1 receptor (CSF-1R) inhibitors
US11530216B2 (en) 2020-12-23 2022-12-20 Genzyme Corporation Deuterated colony stimulating factor-1 receptor (CSF-1R) inhibitors
EP4252853A3 (en) * 2017-03-31 2023-12-13 Aurigene Oncology Limited Compounds and compositions for treating hematological disorders
US11981685B2 (en) 2014-01-13 2024-05-14 Aurigene Oncology Limited Bicyclic heterocyclyl derivatives as IRAK4 inhibitors

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017176804A1 (en) * 2016-04-04 2017-10-12 Massachusetts Institute Of Technology Compositions of crystallized hydrophobic compounds and methods of making and using same
EP3833762A4 (en) 2018-08-09 2022-09-28 Verseau Therapeutics, Inc. OLIGONUCLEOTIDE COMPOSITIONS FOR TARGETING CCR2 AND CSF1R AND THEIR USES
WO2021047677A1 (zh) * 2019-09-12 2021-03-18 中国科学院上海药物研究所 一类irak4激酶抑制剂及其制备和应用
CN112479897B (zh) * 2020-12-07 2022-11-04 万华化学集团股份有限公司 一种1,3-环己二甲胺的制备工艺
CN117384110A (zh) * 2023-10-16 2024-01-12 奥盖尼克材料(苏州)有限公司 一种2-氨基苯并恶唑-6-腈的制备方法

Citations (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3536809A (en) 1969-02-17 1970-10-27 Alza Corp Medication method
US3598123A (en) 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3845770A (en) 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3916899A (en) 1973-04-25 1975-11-04 Alza Corp Osmotic dispensing device with maximum and minimum sizes for the passageway
US4008719A (en) 1976-02-02 1977-02-22 Alza Corporation Osmotic system having laminar arrangement for programming delivery of active agent
US5059595A (en) 1989-03-22 1991-10-22 Bioresearch, S.P.A. Pharmaceutical compositions containing 5-methyltetrahydrofolic acid, 5-formyltetrahydrofolic acid and their pharmaceutically acceptable salts in controlled-release form active in the therapy of organic mental disturbances
US5073543A (en) 1988-07-21 1991-12-17 G. D. Searle & Co. Controlled release formulations of trophic factors in ganglioside-lipsome vehicle
US5120548A (en) 1989-11-07 1992-06-09 Merck & Co., Inc. Swelling modulated polymeric drug delivery device
US5354556A (en) 1984-10-30 1994-10-11 Elan Corporation, Plc Controlled release powder and process for its preparation
US5591767A (en) 1993-01-25 1997-01-07 Pharmetrix Corporation Liquid reservoir transdermal patch for the administration of ketorolac
US5639480A (en) 1989-07-07 1997-06-17 Sandoz Ltd. Sustained release formulations of water soluble peptides
US5639476A (en) 1992-01-27 1997-06-17 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
US5674533A (en) 1994-07-07 1997-10-07 Recordati, S.A., Chemical And Pharmaceutical Company Pharmaceutical composition for the controlled release of moguisteine in a liquid suspension
US5709874A (en) 1993-04-14 1998-01-20 Emory University Device for local drug delivery and methods for using the same
US5733566A (en) 1990-05-15 1998-03-31 Alkermes Controlled Therapeutics Inc. Ii Controlled release of antiparasitic agents in animals
US5739108A (en) 1984-10-04 1998-04-14 Monsanto Company Prolonged release of biologically active polypeptides
US5759542A (en) 1994-08-05 1998-06-02 New England Deaconess Hospital Corporation Compositions and methods for the delivery of drugs by platelets for the treatment of cardiovascular and other diseases
US5840674A (en) 1990-11-01 1998-11-24 Oregon Health Sciences University Covalent microparticle-drug conjugates for biological targeting
US5891474A (en) 1997-01-29 1999-04-06 Poli Industria Chimica, S.P.A. Time-specific controlled release dosage formulations and method of preparing same
US5900252A (en) 1990-04-17 1999-05-04 Eurand International S.P.A. Method for targeted and controlled release of drugs in the intestinal tract and more particularly in the colon
US5922356A (en) 1996-10-09 1999-07-13 Sumitomo Pharmaceuticals Company, Limited Sustained release formulation
US5972366A (en) 1994-11-28 1999-10-26 The Unites States Of America As Represented By The Secretary Of The Army Drug releasing surgical implant or dressing material
US5972891A (en) 1992-12-07 1999-10-26 Takeda Chemical Industries, Ltd. Sustained-release preparation
US5980945A (en) 1996-01-16 1999-11-09 Societe De Conseils De Recherches Et D'applications Scientifique S.A. Sustained release drug formulations
US5985307A (en) 1993-04-14 1999-11-16 Emory University Device and method for non-occlusive localized drug delivery
US5993855A (en) 1995-09-18 1999-11-30 Shiseido Company, Ltd. Delayed drug-releasing microspheres
US6004534A (en) 1993-07-23 1999-12-21 Massachusetts Institute Of Technology Targeted polymerized liposomes for improved drug delivery
US6039975A (en) 1995-10-17 2000-03-21 Hoffman-La Roche Inc. Colon targeted delivery system
US6045830A (en) 1995-09-04 2000-04-04 Takeda Chemical Industries, Ltd. Method of production of sustained-release preparation
US6048736A (en) 1998-04-29 2000-04-11 Kosak; Kenneth M. Cyclodextrin polymers for carrying and releasing drugs
US6060082A (en) 1997-04-18 2000-05-09 Massachusetts Institute Of Technology Polymerized liposomes targeted to M cells and useful for oral or mucosal drug delivery
US6071495A (en) 1989-12-22 2000-06-06 Imarx Pharmaceutical Corp. Targeted gas and gaseous precursor-filled liposomes
US6087324A (en) 1993-06-24 2000-07-11 Takeda Chemical Industries, Ltd. Sustained-release preparation
US6113943A (en) 1996-10-31 2000-09-05 Takeda Chemical Industries, Ltd. Sustained-release preparation capable of releasing a physiologically active substance
US6120751A (en) 1997-03-21 2000-09-19 Imarx Pharmaceutical Corp. Charged lipids and uses for the same
US6131570A (en) 1998-06-30 2000-10-17 Aradigm Corporation Temperature controlling device for aerosol drug delivery
US6139865A (en) 1996-10-01 2000-10-31 Eurand America, Inc. Taste-masked microcapsule compositions and methods of manufacture
US6197350B1 (en) 1996-12-20 2001-03-06 Takeda Chemical Industries, Ltd. Method of producing a sustained-release preparation
US6248363B1 (en) 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US6253872B1 (en) 1996-05-29 2001-07-03 Gmundner Fertigteile Gesellschaft M.B.H & Co., Kg Track soundproofing arrangement
US6264970B1 (en) 1996-06-26 2001-07-24 Takeda Chemical Industries, Ltd. Sustained-release preparation
US6267981B1 (en) 1995-06-27 2001-07-31 Takeda Chemical Industries, Ltd. Method of producing sustained-release preparation
US6271359B1 (en) 1999-04-14 2001-08-07 Musc Foundation For Research Development Tissue-specific and pathogen-specific toxic agents and ribozymes
US6274552B1 (en) 1993-03-18 2001-08-14 Cytimmune Sciences, Inc. Composition and method for delivery of biologically-active factors
US6316652B1 (en) 1995-06-06 2001-11-13 Kosta Steliou Drug mitochondrial targeting agents
US6419961B1 (en) 1996-08-29 2002-07-16 Takeda Chemical Industries, Ltd. Sustained release microcapsules of a bioactive substance and a biodegradable polymer
US6589548B1 (en) 1998-05-16 2003-07-08 Mogam Biotechnology Research Institute Controlled drug delivery system using the conjugation of drug to biodegradable polyester
US6613358B2 (en) 1998-03-18 2003-09-02 Theodore W. Randolph Sustained-release composition including amorphous polymer
US6740634B1 (en) 1998-01-16 2004-05-25 Takeda Chemical Industries, Ltd. Sustained release compositions, process for producing the same and utilization thereof

Family Cites Families (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4104385A (en) 1976-08-19 1978-08-01 Sterling Drug Inc. Cyclic alkylidenyl N-[6-(amino)-3-pyridazinyl]aminomethylenemalonates
FR2687932A1 (fr) 1992-02-27 1993-09-03 Oreal Dispersion huile-dans-l'eau susceptible de former des films composites.
IL135176A0 (en) * 1997-11-10 2001-05-20 Bristol Myers Squibb Co Benzothiazole derivatives and pharmaceutical compositions containing the same
IL151045A0 (en) * 2000-02-07 2003-04-10 Abbott Gmbh & Co Kg 2-benzothiazolyl urea derivatives and their use as protein kinase inhibitors
DK1392306T3 (da) * 2001-06-06 2008-05-19 Aventis Pharma Ltd Substituerede tetrahydroisoquinoliner til anvendelse i behandlingen af inflammatoriske sygdomme
US7112435B1 (en) 2002-08-07 2006-09-26 Ambit Biosciences Corporation Uncoupling of DNA insert propagation and expression of protein for phage display
AU2003231359B2 (en) * 2002-04-16 2009-04-30 Teijin Limited Piperidine derivatives having CCR3 antagonism
FR2851563B1 (fr) 2003-02-26 2005-04-22 Sod Conseils Rech Applic Nouveaux derives de benzimidazole et d'imidazo-pyridine et leur utilisation en tant que medicament
BRPI0408332A (pt) 2003-03-14 2006-03-21 Ono Pharmaceutical Co derivados heterocìclicos contendo nitrogênio e medicamentos contendo os mesmos como ingrediente ativo
US7531553B2 (en) * 2003-03-21 2009-05-12 Amgen Inc. Heterocyclic compounds and methods of use
US20070099938A1 (en) 2003-10-24 2007-05-03 Ono Pharmaceutical Co., Ltd. Antistress drug and medical use thereof
DE10349587A1 (de) * 2003-10-24 2005-05-25 Merck Patent Gmbh Benzimidazolylderivate
WO2005058874A1 (en) 2003-12-18 2005-06-30 Tibotec Pharmaceuticals Ltd. 5- or 6-substituted benzimidazole derivatives as inhibitors of respiratory syncytial virus replication
AR046959A1 (es) 2003-12-18 2006-01-04 Tibotec Pharm Ltd Morfolinilo que contiene bencimidazoles como inhibidores de la replicacion del virus sincitial respiratorio
US7470712B2 (en) 2004-01-21 2008-12-30 Bristol-Myers Squibb Company Amino-benzazoles as P2Y1 receptor inhibitors
WO2005100373A2 (en) * 2004-04-13 2005-10-27 Ranbaxy Laboratories Limited Monosaccharide derivatives as anti-cancer and anti-inflammatory agents
US6969498B1 (en) * 2004-05-07 2005-11-29 Riley Medical, Inc. Surgical instrument bracket assembly
JP2006070014A (ja) 2004-08-04 2006-03-16 Hisamitsu Medical Kk ２−アミノベンゾチアゾール誘導体
CA2612263C (en) 2005-06-20 2015-04-14 Tibotec Pharmaceuticals Ltd. 1-(2-amino-3-(substituted alkyl)-3h-benzimidazolylmethyl)-3-subtituted-1,3-dihydro-benzoimidazol-2-ones with activity on respiratory syncytial virus
US20080146536A1 (en) 2005-08-16 2008-06-19 Pharmacopeia, Inc. 2-Aminoimidazopyridines for treating neurodegenerative diseases
NZ571566A (en) * 2006-03-17 2011-07-29 Ambit Biosciences Corp Imidazolothiazole compounds for the treatment of disease
KR101280333B1 (ko) * 2006-03-28 2013-07-02 하이 포인트 파마슈티칼스, 엘엘씨 히스타민 ｈ３ 수용체 활성을 갖는 벤조티아졸
EP2405272B1 (en) 2006-06-30 2015-01-14 DiscoveRx Corporation Detectable nucleic acid tag
WO2008121687A2 (en) 2007-03-28 2008-10-09 Array Biopharma Inc. Imidazo[1,2-a]pyridine compounds as receptor tyrosine kinase inhibitors
CN101754965B (zh) * 2007-05-21 2014-03-19 诺华股份有限公司 Csf-1r抑制剂、组合物及使用方法
CN101801379A (zh) * 2007-10-18 2010-08-11 诺瓦提斯公司 治疗癌症和骨疾病的csf-1r抑制剂
US8153813B2 (en) 2007-12-20 2012-04-10 Abbott Laboratories Benzothiazole and benzooxazole derivatives and methods of use
US7863291B2 (en) 2008-04-23 2011-01-04 Bristol-Myers Squibb Company Quinuclidine compounds as alpha-7 nicotinic acetylcholine receptor ligands
US8309577B2 (en) 2008-04-23 2012-11-13 Bristol-Myers Squibb Company Quinuclidine compounds as α-7 nicotinic acetylcholine receptor ligands
MX2011004625A (es) 2008-11-03 2011-07-20 Syntarga Bv Analogos cc-1065 novedosos y sus conjugados.
UY32470A (es) 2009-03-05 2010-10-29 Boehringer Ingelheim Int Derivados de 2-{2-cloro-5-[(sustituido) metil]fenilamino} -1-metil]fenilamino}-1-metilbencimidazol-5-carboxamidas-n-(sustituidas) y sus sales fisiológicamente aceptables, composiciones conteniéndolos y aplicaciones
US8513291B2 (en) 2010-06-01 2013-08-20 Angion Biomedica Corp. Cytochrome P450 inhibitors and uses thereof
EP2611784A4 (en) 2010-08-05 2014-01-08 Amgen Inc BENZIMIDAZOLE AND AZABENEZIMIDAZOLE COMPOUNDS FOR INHIBITING THE ANAPLASTIC LYMPHOMINE KINASE
WO2012088438A1 (en) 2010-12-22 2012-06-28 Eutropics Pharmaceuticals, Inc. Compositions and methods useful for treating diseases

Patent Citations (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3536809A (en) 1969-02-17 1970-10-27 Alza Corp Medication method
US3598123A (en) 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3845770A (en) 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3916899A (en) 1973-04-25 1975-11-04 Alza Corp Osmotic dispensing device with maximum and minimum sizes for the passageway
US4008719A (en) 1976-02-02 1977-02-22 Alza Corporation Osmotic system having laminar arrangement for programming delivery of active agent
US5739108A (en) 1984-10-04 1998-04-14 Monsanto Company Prolonged release of biologically active polypeptides
US5354556A (en) 1984-10-30 1994-10-11 Elan Corporation, Plc Controlled release powder and process for its preparation
US5073543A (en) 1988-07-21 1991-12-17 G. D. Searle & Co. Controlled release formulations of trophic factors in ganglioside-lipsome vehicle
US5059595A (en) 1989-03-22 1991-10-22 Bioresearch, S.P.A. Pharmaceutical compositions containing 5-methyltetrahydrofolic acid, 5-formyltetrahydrofolic acid and their pharmaceutically acceptable salts in controlled-release form active in the therapy of organic mental disturbances
US5639480A (en) 1989-07-07 1997-06-17 Sandoz Ltd. Sustained release formulations of water soluble peptides
US5120548A (en) 1989-11-07 1992-06-09 Merck & Co., Inc. Swelling modulated polymeric drug delivery device
US6071495A (en) 1989-12-22 2000-06-06 Imarx Pharmaceutical Corp. Targeted gas and gaseous precursor-filled liposomes
US5900252A (en) 1990-04-17 1999-05-04 Eurand International S.P.A. Method for targeted and controlled release of drugs in the intestinal tract and more particularly in the colon
US5733566A (en) 1990-05-15 1998-03-31 Alkermes Controlled Therapeutics Inc. Ii Controlled release of antiparasitic agents in animals
US5840674A (en) 1990-11-01 1998-11-24 Oregon Health Sciences University Covalent microparticle-drug conjugates for biological targeting
US5639476A (en) 1992-01-27 1997-06-17 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
US5972891A (en) 1992-12-07 1999-10-26 Takeda Chemical Industries, Ltd. Sustained-release preparation
US5591767A (en) 1993-01-25 1997-01-07 Pharmetrix Corporation Liquid reservoir transdermal patch for the administration of ketorolac
US6274552B1 (en) 1993-03-18 2001-08-14 Cytimmune Sciences, Inc. Composition and method for delivery of biologically-active factors
US5985307A (en) 1993-04-14 1999-11-16 Emory University Device and method for non-occlusive localized drug delivery
US5709874A (en) 1993-04-14 1998-01-20 Emory University Device for local drug delivery and methods for using the same
US6376461B1 (en) 1993-06-24 2002-04-23 Takeda Chemical Industries, Ltd. Sustained-release preparation
US6087324A (en) 1993-06-24 2000-07-11 Takeda Chemical Industries, Ltd. Sustained-release preparation
US6004534A (en) 1993-07-23 1999-12-21 Massachusetts Institute Of Technology Targeted polymerized liposomes for improved drug delivery
US5674533A (en) 1994-07-07 1997-10-07 Recordati, S.A., Chemical And Pharmaceutical Company Pharmaceutical composition for the controlled release of moguisteine in a liquid suspension
US5759542A (en) 1994-08-05 1998-06-02 New England Deaconess Hospital Corporation Compositions and methods for the delivery of drugs by platelets for the treatment of cardiovascular and other diseases
US5972366A (en) 1994-11-28 1999-10-26 The Unites States Of America As Represented By The Secretary Of The Army Drug releasing surgical implant or dressing material
US6316652B1 (en) 1995-06-06 2001-11-13 Kosta Steliou Drug mitochondrial targeting agents
US6267981B1 (en) 1995-06-27 2001-07-31 Takeda Chemical Industries, Ltd. Method of producing sustained-release preparation
US6045830A (en) 1995-09-04 2000-04-04 Takeda Chemical Industries, Ltd. Method of production of sustained-release preparation
US5993855A (en) 1995-09-18 1999-11-30 Shiseido Company, Ltd. Delayed drug-releasing microspheres
US6039975A (en) 1995-10-17 2000-03-21 Hoffman-La Roche Inc. Colon targeted delivery system
US5980945A (en) 1996-01-16 1999-11-09 Societe De Conseils De Recherches Et D'applications Scientifique S.A. Sustained release drug formulations
US6253872B1 (en) 1996-05-29 2001-07-03 Gmundner Fertigteile Gesellschaft M.B.H & Co., Kg Track soundproofing arrangement
US6264970B1 (en) 1996-06-26 2001-07-24 Takeda Chemical Industries, Ltd. Sustained-release preparation
US6419961B1 (en) 1996-08-29 2002-07-16 Takeda Chemical Industries, Ltd. Sustained release microcapsules of a bioactive substance and a biodegradable polymer
US6139865A (en) 1996-10-01 2000-10-31 Eurand America, Inc. Taste-masked microcapsule compositions and methods of manufacture
US5922356A (en) 1996-10-09 1999-07-13 Sumitomo Pharmaceuticals Company, Limited Sustained release formulation
US6113943A (en) 1996-10-31 2000-09-05 Takeda Chemical Industries, Ltd. Sustained-release preparation capable of releasing a physiologically active substance
US6699500B2 (en) 1996-10-31 2004-03-02 Takeda Chemical Industries, Ltd. Sustained-release preparation capable of releasing a physiologically active substance
US6197350B1 (en) 1996-12-20 2001-03-06 Takeda Chemical Industries, Ltd. Method of producing a sustained-release preparation
US5891474A (en) 1997-01-29 1999-04-06 Poli Industria Chimica, S.P.A. Time-specific controlled release dosage formulations and method of preparing same
US6120751A (en) 1997-03-21 2000-09-19 Imarx Pharmaceutical Corp. Charged lipids and uses for the same
US6060082A (en) 1997-04-18 2000-05-09 Massachusetts Institute Of Technology Polymerized liposomes targeted to M cells and useful for oral or mucosal drug delivery
US6740634B1 (en) 1998-01-16 2004-05-25 Takeda Chemical Industries, Ltd. Sustained release compositions, process for producing the same and utilization thereof
US6613358B2 (en) 1998-03-18 2003-09-02 Theodore W. Randolph Sustained-release composition including amorphous polymer
US6048736A (en) 1998-04-29 2000-04-11 Kosak; Kenneth M. Cyclodextrin polymers for carrying and releasing drugs
US6589548B1 (en) 1998-05-16 2003-07-08 Mogam Biotechnology Research Institute Controlled drug delivery system using the conjugation of drug to biodegradable polyester
US6131570A (en) 1998-06-30 2000-10-17 Aradigm Corporation Temperature controlling device for aerosol drug delivery
US6271359B1 (en) 1999-04-14 2001-08-07 Musc Foundation For Research Development Tissue-specific and pathogen-specific toxic agents and ribozymes
US6248363B1 (en) 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions

Non-Patent Citations (43)

* Cited by examiner, † Cited by third party
Title
BAIOCCHI G ET AL., CANCER, vol. 67, 1991, pages 990 - 996
BAUKNECHT ET AL., CANCER DETECT. PREV., vol. 18, 1994, pages 231 - 239
BIOCHEM., vol. 11, 1972, pages 942 - 944
BLUME-JENSEN, NATURE, vol. 411, no. 17, 2001, pages 355 - 365
BLUME-JENSEN; HUNTER, NATURE, vol. 411, no. 17, 2001, pages 355 - 365
CONWAT ET AL., JPET, vol. 326, 2008, pages 41 - 50
CURTAIN ET AL., J CLIN. ONCOL., vol. 24, no. 26, 2006, pages 4340 - 4346
DUENSING ET AL., CANCER INVESTIGATION, vol. 22, no. 1, 2004, pages 106 - 116
FABIAN ET AL., NATURE BIOTECHNOLOGY, vol. 23, 2005, pages 329 - 336
FOSTER ET AL., ADV. DRUG RES., vol. 14, 1985, pages 1 - 36
GIORGI, VERWEIJ, MOL. CANCER THER., vol. 4, no. 3, 2005, pages 495 - 501
GORDON, DRUG METAB. DISPOS., vol. 15, 1987, pages 589
GREEN, T.W.; P.G.M. WUTZ: "Protective Groups in Organic Synthesis", 1991, WILEY-1NTERSCIENCE
HEINRICH, MINI-REVIEWS IN MEDICINAL CHEMISTRY, vol. 4, no. 3, 2004, pages 255 - 271
J. ORG. CHEM., vol. 72, no. 1, 2007, pages 23A - 24A
KIRMA ET AL., CANCER RES., 2007
KIYOI ET AL., INT J HEMATOL, vol. 82, 2005, pages 85 - 92
KLUGER ET AL., CLIN. CANC. RES., vol. 10, 2004, pages 173 - 177
KRAUSE; VAN ETTEN, NENGL JMED, vol. 353, no. 2, 2005, pages 172 - 187
KUSHNER ET AL., CAN. J. PHYSIOL. PHARMACOL., vol. 77, 1999, pages 79 - 88
LCVIS ET AL., INT J HEMATOL., vol. 82, 2005, pages 100 - 107
LIJINSKY, FOOD COSMET. TOXICOL., vol. 20, 1982, pages 393
LIJINSKY, J. NAT. CANCER INST., vol. 69, 1982, pages 1127
LIPTON, J. SUPPORT. ONCOL., vol. 2, 2004, pages 205 - 220
MANGOLD, MUTATION RES., vol. 308, 1994, pages 33
MARCH: "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 1992, WILEY INTERSCIENCE
MOLINOS-GOMEZ ET AL., TETRAHEDRON, vol. 61, 2005, pages 9075
MROCZKO ET AL., CLIN. CHEM. LAB. MED., vol. 43, 2005, pages 146 - 50
MROCZKO ET AL., CLIN. CHIM. ACTA, vol. 380, 2007, pages 208 - 212
MULLER-TIDOW ET AL., CLIN CANCER RES, vol. 10, 2004, pages 1241 - 1249
OHNO ET AL., EUR. J. IMMUNOL., vol. 38, 2008, pages 283 - 291
PLOWMAN ET AL., DN&P, vol. 7, 1994, pages 334 - 339
PRICEMAN ET AL., BLOOD, vol. 115, no. 7, 2010, pages 1461 - 1471
RITCHLIN ET AL., J. CLIN. INVEST., vol. 111, 2003, pages 821 - 831
ROLLAND ET AL., J. IMMUNOL., vol. 174, 2005, pages 3067 - 3071
SAPI ET AL., EXP. BIOL. MED., vol. 229, 2004, pages 1 - 11
SCHOLL ET AL., J. NATL. CANCER INST., vol. 86, 1994, pages 120 - 126
SCOTT ET AL., RHEUMATOLOGY, vol. 39, 2000, pages 122 - 132
SMITH; MARCH: "Advanced Organic Chemistry", 2001
STILL ET AL., 1. ORG. CHEM., vol. 43, 1978, pages 2923
TANG ET AL., J. CELL. BIOCHEM., vol. 44, 1990, pages 189 - 198
WHARTENBY ET AL., PNAS, vol. 102, 2005, pages 16741 - 16746
ZELLO, METABOLISM, vol. 43, 1994, pages 487

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